In addition to studying the pathophysiology of glaucoma, our focus is on the development of potential treatments. Retinal ganglion cell (RGC) loss is a hallmark of glaucoma and optic neuropathies. Previously we demonstrated that intravitreal injection of small extracellular vesicles (sEV), produced by bone marrow-derived mesenchymal stem cells (BMSC), but not fibroblast-produced sEV, provided statistically significant RGC neuroprotection and regeneration of their axons, while partially preventing RGC dysfunction and axonal loss in rat models of optic nerve crush (ONC) and glaucoma (laser or microbead). To determine if BMSC-derived sEV promote RGC neuroprotection in the long-term, we used DBA/2J mice, a genetic model of glaucoma. DBA/2J mice developed chronic ocular hypertension beginning from 6 months. Monthly delivery of BMSC sEV, but not fibroblast sEV, provided significant neuroprotective effects for RGCs whilst significantly reducing the number of degenerating axons seen in the optic nerve in 12-month-old mice. BMSC sEV partially preserved RGC function in 6-month-old mice but provided no benefit at 9 and 12 months. These data suggest that BMSC sEV are an effective neuroprotective treatment in a chronic, 1-year model of glaucoma, preserving RGC numbers and protecting against axonal degeneration. Our data suggest that sEV-derived miRNAs play an important role in RGC neuroprotection, and several candidate miRNAs participating in neuroprotection have been identified. To narrow down the list of candidate miRNAs, we continued the characterization of changes in the spectrum of miRNAs in RGCs after ONC. Using the same ONC model as above, intravitreal injection of adeno-associated viral vectors (AAVs) to express a number of candidate proteins is being explored to provide neuroprotection and/or axon regeneration to injured RGC. Among tested proteins, activating transcription factor 3 (ATF3) provided the best positive effects. The level of ATF3 is elevated in RGCs following optic nerve crush. Overexpression of ATF3 by intravitreal injection of recombinant AAV two weeks prior to optic nerve crush promoted RGC survival, as assessed by RGC counting, and preserved RGC functions, as assessed by electroretinogram recordings of positive scotopic threshold response. Moreover, overexpression of ATF3 alone or following downregulation of PTEN, a negative regulator of the mTOR pathway, promoted RGC axon regeneration after optic nerve crush. These results reveal a neuroprotective effect of ATF3 in the central nervous system following injury and identify ATF3 as a promising agent for potential treatments of optic neuropathies.